<p>Glioblastoma (GBM), the most aggressive type of primary brain tumor in adults, is characterized by a poor prognosis and considerable resistance to current therapies. Traditional treatment approaches—surgery, radiation, and chemotherapy—offer few clinical benefits and are often linked to increased recurrence rates and significant adverse effects. This underscores the urgent need for novel therapeutic strategies. Targeting the transforming growth factor-beta (TGF-β) signaling pathway is a viable strategy. TGF-β acts as a tumor suppressor during the first stages of cancer but promotes tumor progression, angiogenesis, immune evasion, and the creation of an immunosuppressive tumor microenvironment in GBM. The deregulation of TGF-β signaling has been shown to interact with essential carcinogenic pathways, including the Wnt/β-catenin, PI3K/AKT, and Notch pathways, therefore aggravating GBM pathogenesis. TGF-β plays a pivotal role in controlling glioma stem cells and influencing the permeability of the blood–brain barrier, making it an attractive target for therapeutic intervention. Novel treatment approaches, including small-molecule inhibitors and monoclonal antibodies, as well as the use of phytochemicals such as flavonoids, quercetin, and other phytochemicals targeting specific elements of the TGF-β signaling pathway, have shown encouraging results in preclinical investigations and early-stage clinical trials. These novel strategies may enhance clinical outcomes and mitigate treatment limitations in GBM therapy by leveraging this system’s combined tumor-suppressive and immune-regulatory properties.</p>